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J. Biol. Chem., Vol. 280, Issue 11, 9855-9864, March 18, 2005

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Depletion of Mitochondrial DNA Causes Impaired Glucose Utilization and Insulin Resistance in L6 GLUT4myc Myocytes^*

Seung Y. Park, Guem H. Choi, Hyo I. Choi, Jiwon Ryu, Chan Y. Jung, and Wan Lee¶

From the Department of Biochemistry, College of Medicine, Dongguk University, Kyungju 780-714, Korea, and the Biophysics Laboratory, Veterans Affairs Medical Center, Department of Physiology and Biophysics, School of Medicine, State University of New York, Buffalo, New York 14215

Mitochondrial dysfunction contributes to a number of human diseases, such as hyperlipidemia, obesity, and diabetes. The mutation and reduction of mitochondrial DNA (mtDNA) have been suggested as factors in the pathogenesis of diabetes. To elucidate the association of cellular mtDNA content and insulin resistance, we produced L6 GLUT4myc myocytes depleted of mtDNA by long term treatment with ethidium bromide. L6 GLUT4myc cells cultured with 0.2 µg/ml ethidium bromide (termed depleted cells) revealed a marked decrease in cellular mtDNA and ATP content, concomitant with a lack of mRNAs encoded by mtDNA. Interestingly, the mtDNA-depleted cells showed a drastic decrease in basal and insulin-stimulated glucose uptake, indicating that L6 GLUT4myc cells develop impaired glucose utilization and insulin resistance. The repletion of mtDNA normalized basal and insulin-stimulated glucose uptake. The mRNA level and expression of insulin receptor substrate (IRS)-1 associated with insulin signaling were decreased by 76 and 90% in the depleted cells, respectively. The plasma membrane (PM) GLUT4 in the basal state was decreased, and the insulin-stimulated GLUT4 translocation to the PM was drastically reduced by mtDNA depletion. Moreover, insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B were drastically reduced in the depleted cells. Those changes returned to control levels after mtDNA repletion. Taken together, our data suggest that PM GLUT4 content and insulin signal pathway intermediates are modulated by the alteration of cellular mtDNA content, and the reductions in the expression of IRS-1 and insulin-stimulated phosphorylation of IRS-1 and Akt2/protein kinase B are associated with insulin resistance in the mtDNA-depleted L6 GLUT4myc myocytes.

Received for publication, August 16, 2004 , and in revised form, November 18, 2004.

^* This study was supported by Korea Health 21 R&D Project, Ministry of Health and Welfare, Republic of Korea, Grants 02-PJ1-PG1-CH04-0001 and 00-PJ3-PG6-GN07-0001 and the American Diabetes Association and Buffalo Veterans Affairs Medical Center Medical Research Services. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry, College of Medicine, Dongguk University, Kyungju 780-714, Korea. Tel.: 82-54-770-2409; Fax: 82-54-770-2447; E-mail: wanlee{at}mail.dongguk.ac.kr.

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